Aqueous fluids account for approximately half oa normal adult's body weight. These fluids contain osmotically active solutes. The proper concentrations of solutes within bodily fluids are maintained within narrow limits despite large variations of both solute and water intake by changes in the volume of water excreted per day. Thus, proper renal processing of aqueous fluids, including modulation of water excretion, is critically important to the maintenance of good health.
Renal processing of the body's solutes and water content first involves filtering of blood at lomeruli to separate retained blood cells and proteins from filtered solutes and water. The majority of the filtered solutes and water are returned to the body's circulation via selective absorption by renal tubules. In the proximal portion of renal tubules, water reabsorption occurs as a result of active reabsorption f solutes. In contrast, in distal portions of the tubules, solute and water reabsorption occur by separate processes. When an excess of body water is present, there is reabsorption of body solutes and excess water flows through the distal nephron to the bladder as dilute urine. In periods of dehydration, water is osmotically reabsorbed such that a concentrated hypertnic urine is formed. Osmotic reabsorption of water in the distal nephron segment, called the collecting duct, is modulated by antidiuretic hormone (ADH). Changes in collecting duct water permeability are accomplished through control of the water permeability of the apical membranes of epithelial cells that line this segment. ADH causes the insertion of water channels into epithelial cell apical membranes. These water channels were originally contained in vesicles within the cytoplasm of these epithelial cells. ADH causes water channel insertion by fusion of the water channel-containing vesicles with the apical membrane. Removal of the ADH stimuli causes removal of water channels from the apical membrane by retrieval of the water channel-containing membrane into the epithelial cell cytoplasm.
A variety of diseases are associated with retention of excess body water. These include, for example, liver failure, heart disease and syndrome of inappropriate ADH secretion (SIADH). These diseases are difficult to manage therapeutically because of the kidney's dissociation of solute and water reabsorption, as discussed above.
One of the major problems preventing effective removal of excess body water in these diseases in the lack of ability to selectively block renal water reabsorption. Presently, these diseases are treated with a variety of diuretic agents. However, currently available diuretics block renal tubular water reabsorption by inhibiting tubular solute reabsorption. Thus, in order to remove excess body water, there is an obligatory loss of large amounts of body solutes that results in the depletion of body ionic stores, especially sodium, potassium and chloride ions.
It is apparent, therefore, that there has been a longstanding need for better and more selective diuretics. Despite the need, it has been extremely difficult, or impossible, to screen compounds for their diuretic potency and selectivity in blocking water flow across ADH water channels. This is largely due to the fact that water flow through the water channels and lipid bilayers is so rapid that it nearly precludes any practical way of measuring such flow.